1. Field of the Invention
The present invention relates to aminoalkyl substituted pyrrolo[3,2-e]pyridine and pyrrolo[2,3-b]pyrimidine derivatives, pharmaceutical compositions containing such compounds, and their use for the treatment of psychiatric disorders and neurological diseases, including major depression, anxiety-related disorders, post-traumatic stress disorder, supranuclear palsy and feeding disorders, as well as treatment of immunological, cardiovascular or heart-related diseases and colonic hypersensitivity associated with psychopathological disturbance and stress.
2. Description of the Related Art
Corticotropin releasing factor (herein referred to as CRF), a 41 amino acid peptide, is the primary physiological regulator of proopiomelanocortin (POMC) derived peptide secretion from the anterior pituitary gland [J. Rivier et al., Proc. Nat. Acad. Sci. (USA) 80:4851 (1983); W. Vale et al., Science 213:1394 (1981)]. In addition to its endocrine role at the pituitary gland, immunohistochemical localization of CRF has demonstrated that the hormone has a broad extrahypothalamic distribution in the central nervous system and produces a wide spectrum of autonomic, electrophysiological and behavioral effects consistent with a neurotransmitter or neuromodulator role in brain [W. Vale et al., Rec. Prog. Horm. Res. 39:245 (1983); G. F. Koob, Persp. Behav. Med. 2:39 (1985); E. B. De Souza et al., J. Neurosci. 5:3189 (1985)]. There is also evidence that CRF plays a significant role in integrating the response of the immune system to physiological, psychological, and immunological stressors [J. E. Blalock, Physiological Reviews 69:1 (1989); J. E. Morley, Life Sci. 41:527 (1987)].
Clinical data provide evidence that CRF has a role in psychiatric disorders and neurological diseases including depression, anxiety-related disorders and feeding disorders. A role for CRF has also been postulated in the etiology and pathophysiology of Alzheimer""s disease, Parkinson""s disease, Huntington""s disease, progressive supranuclear palsy and amyotrophic lateral sclerosis as they relate to the dysfunction of CRF neurons in the central nervous system [for review see E. B. De Souza, Hosp. Practice 23:59 (1988)].
In affective disorder, or major depression, the concentration of CRF is significantly increased in the cerebral spinal fluid (CSF) of drug-free individuals [C. B. Nemeroff et al., Science 226:1342 (1984); C. M. Banki et al., Am. J. Psychiatry 144:873 (1987); R. D. France et al., Biol. Psychiatry 28:86 (1988); M. Arato et al., Biol Psychiatry 25:355 (1989). Furthermore, the density of CRF receptors is significantly decreased in the frontal cortex of suicide victims, consistent with a hypersecretion of CRF [C. B. Nemeroff et al., Arch. Gen. Psychiatry 45:577 (1988)]. In addition, there is a blunted adrenocorticotropin (ACTH) response to CRF (i.v. administered) observed in depressed patients [P. W. Gold et al., Am J. Psychiatry 141:619 (1984); F. Holsboer et al., Psychoneuroendocrinology 9:147(1984); P. W. Gold et al., New Eng. J. Med. 314:1129 (1986)]. Preclinical studies in rats and non-human primates provide additional support for the hypothesis that hypersecretion of CRF may be involved in the symptoms seen in human depression [R. M. Sapolsky, Arch. Gen. Psychiatry 46:1047 (1989)]. There is preliminary evidence that tricyclic antidepressants can alter CRF levels and thus modulate the numbers of CRF receptors in brain [Grigoriadis et al., Neuropsychopharmacology 2:53 (1989)].
There has also been a role postulated for CRF in the etiology of anxiety-related disorders. CRF produces anxiogenic effects in animals and interactions between benzodiazepine/non-benzodiazepine anxiolytics and CRF have been demonstrated in a variety of behavioral anxiety models [D. R. Britton et al., Life Sci. 31:363 (1982); C. W. Berridge and A. J. Dunn Regul. Peptides 16:83 (1986)]. Preliminary studies using the putative CRF receptor antagonist xcex1-helical ovine CRF (9-41) in a variety of behavioral paradigms demonstrate that the antagonist produces xe2x80x9canxiolytic-likexe2x80x9d effects that are qualitatively similar to the benzodiazepines [C. W Berridge and A. J. Dunn Horm. Behav. 21:393 (1987), Brain Research Reviews 15:71 (1990)]. Neurochemical, endocrine and receptor binding studies have all demonstrated interactions between CRF and benzodiazepine anxiolytics providing further evidence for the involvement of CRF in these disorders. Chlordiazepoxide attenuates the xe2x80x9canxiogenicxe2x80x9d effects of CRF in both the conflict test [K. T. Britton et al., Psychopharmacology 86:170 (1985); K. T. Britton et al., Psychopharmacology 94:306 (1988)] and in the acoustic startle test [N. R. Swerdlow et al., Psychopharmacology 88:147 (1986)] in rats. The benzodiazepine receptor antagonist (Ro 15-1788), which was without behavioral activity alone in the operant conflict test, reversed the effects of CRF in a dose-dependent manner while the benzodiazepine inverse agonist (FG 7142) enhanced the actions of CRF [K. T. Britton et al., Psychopharmacology 94:306 (1988)].
It has been further postulated that CRF has a role in immunological, cardiovascular or heart-related diseases such as hypertension, tachycardia and congestive heart failure, stroke and osteoporosis. CRF has also been implicated in premature birth, psychosocial dwarfism, stress-induced fever, ulcer, diarrhea, post-operative ileus and colonic hypersensitivity associated with psychopathological disturbance and stress.
The mechanisms and sites of action through which the standard anxiolytics and antidepressants produce their therapeutic effects remain to be elucidated. It has been hypothesized however, that they are involved in the suppression of the CRF hypersecretion that is observed in these disorders. Of particular interest is that preliminary studies examining the effects of a CRF receptor antagonist (xcex1-helical CRF9-41) in a variety of behavioral paradigms have demonstrated that the CRF antagonist produces xe2x80x9canxiolytic-likexe2x80x9d effects qualitatively similar to the benzodiazepines [for review see G. F. Koob and K. T. Britton, In: Corticotropin-Releasing Factor: Basic and Clinical Studies of a Neuropeptide, E. B. De Souza and C. B Nemeroff eds., CRC Press p221 (1990)].
In one aspect, the present invention provides novel compounds which bind to corticotropin releasing factor receptors, thereby altering the anxiogenic effects of CRF secretion. The compounds of the present invention are useful for the treatment of psychiatric disorders and neurological diseases, anxiety-related disorders, post-traumatic stress disorder, supranuclear palsy and feeding disorders as well as treatment of immunological, cardiovascular or heart-related diseases and colonic hypersensitivity associated with psychopathological disturbance and stress in mammals. According to another aspect, the present invention provides novel compounds of Formula I (described below) which are useful as antagonists of the corticotropin releasing factor. The compounds of the present invention exhibit activity as corticotropin releasing factor antagonists and appear to suppress CRF hypersecretion. The present invention also includes pharmaceutical compositions containing such compounds of Formula I, and methods of using such compounds for the suppression of CRF hypersecretion, and/or for the treatment of anxiogenic disorders.
In another aspect, the present invention provides novel compounds, pharmaceutical compositions and methods which may be used in the treatment of affective disorder, anxiety, depression, irritable bowel syndrome, post-traumatic stress disorder, supranuclear palsy, immune suppression, Alzheimer""s disease, gastrointestinal disease, anorexia nervosa or other feeding disorder, drug or alcohol withdrawal symptoms, drug addiction, inflammatory disorder, fertility problems, disorders, the treatment of which can be effected or facilitated by antagonizing CRF, including but not limited to disorders induced or facilitated by CRF, or a disorder selected from inflammatory disorders such as rheumatoid arthritis and osteoarthritis, pain, asthma, psoriasis and allergies; generalized anxiety disorder; panic, phobias, obsessive-compulsive disorder; post-traumatic stress disorder; sleep disorders induced by stress; pain perception such as fibromyalgia; mood disorders such as depression, including major depression, single episode depression, recurrent depression, child abuse induced depression, and postpartum depression; dysthemia; bipolar disorders; cyclothymia; fatigue syndrome; stress-induced headache; cancer, human immunodeficiency virus (HIV) infections; neurodegenerative diseases such as Alzbeimer""s disease, Parkinson""s disease and Huntington""s disease; gastrointestinal diseases such as ulcers, irritable bowel syndrome, Crohn""s disease, spastic colon, diarrhea, and post operative ilius and colonic hypersensitivity associated by psychopathological disturbances or stress; eating disorders such as anorexia and bulimia nervosa; hemorrhagic stress; stress-induced psychotic episodes; euthyroid sick syndrome; syndrome of inappropriate antidiarrhetic hormone (ADR); obesity; infertility; head traumas; spinal cord trauma; ischemic neuronal damage (e.g., cerebral ischemia such as cerebral hippocampal ischemia); excitotoxic neuronal damage; epilepsy; cardiovascular and heart related disorders including hypertension, tachycardia and congestive heart failure; stroke; immune dysfunctions including stress induced immune dysfunctions (e.g., stress induced fevers in humans and the following animal diseases: porcine stress syndrome, bovine shipping fever, equine paroxysmal fibrillation, and dysfunctions induced by confinement in chickens, sheering stress in sheep or human-animal interaction related stress in dogs); muscular spasms; urinary incontinence; senile dementia of the Alzheimer""s type; multiinfarct dementia; amyotrophic lateral sclerosis; chemical dependencies and addictions (e.g., dependencies on alcohol, cocaine, heroin, benzodiazepines, or other drugs); drug and alcohol withdrawal symptoms; osteoporosis; psychosocial dwarfism and hypoglycemia in mammals.
In a further aspect of the invention, the compounds provided by this invention (and especially radiolabeled compounds of this invention) are also useful as standards and reagents in determining the ability of a potential pharmaceutical to bind to the CRF1 receptor.
The novel compounds encompassed by the instant invention can be described by general Formula I: 
wherein
Ar is phenyl, 1- or 2-naphthyl, 2-, 3-, or 4-pyridyl, 2-, 4- or 5-pyrimidinyl, optionally mono-, di-, or tri-substituted with halogen, trifluoromethyl, hydroxy, amino, lower alkylamino, lower dialkylamino, carboxamido, lower alkylcarboxamido, N,N-lower dialkylcarboxamido, lower alkyl, lower alkoxy, with the proviso that at least one of the positions ortho or para to the point of attachment of Ar to the tricyclic ring system is substituted;
R1 is hydrogen, halogen, trifluoromethyl, lower alkyl, or (C1-C6 alkyl)-G1-R2 where G1 is oxygen or sulfur and R2 is hydrogen or C1-C6 alkyl;
W is N or Cxe2x80x94R3 where R3 is hydrogen or lower alkyl;
Q1 is hydrogen, lower alkyl, halogen, lower alkoxy, amino, methylamino, dimethylamino, hydroxymethyl, or SOn(C1-C4 alkyl) where n is 0, 1 or 2, cyano, hydroxy, xe2x80x94C(O) (C1-C4 alkyl), xe2x80x94CHO, xe2x80x94CO2(C1-C4 alkyl), xe2x80x94CO2(C1-C4 alkenyl), or xe2x80x94CO2(C1-C4 alkynyl);
Q2 is hydrogen, lower alkyl, halogen, hydroxymethyl, methoxymethyl, or lower alkoxy;
X is 
wherein
V1 and V2 are CH2, CO, CS, SO2 or CH(lower alkyl), with the proviso that both V1 and V2 cannot both be CO, CS or SO2;
Y1 and Y2 independently represent a bond or lower alkylene;
A1 is NR4R5 wherein R4 and R5 are independently hydrogen or a lower alkyl group which optionally forms a heterocycloalkyl group with Y1;
lower alkanoyl, lower alkylsulfonyl, with the proviso that R4 and R5 cannot both be alkanoyl or alkylsulfonyl; or
NR4R5 taken together form a C3-C6 heterocycloalkyl or a group of the formula: 
xe2x80x83wherein e and f are independently 1, 2 or 3 and the sum of e and f is at least 3; and
G2 is
NR6 wherein R6 is hydrogen or lower alkyl, or
CH(C0-C6 alkylene)xe2x80x94G3xe2x80x94R7 wherein G3 is CONH, CONH(lower alkyl), NH, NH(lower alkyl) and R7 is hydrogen or lower alkyl; or
CONH2, CO[N(lower alkyl)R8] wherein R8 is hydrogen or lower alkyl;
A2 is hydrogen, lower alkyl, (C1-C6 alkylene)xe2x80x94G4xe2x80x94R9 wherein G4 is oxygen or sulfur and R9 is hydrogen, trifluoromethyl or lower alkyl; 
wherein heteroaryl is 2-, 3- or 4-pyridyl, 2-, 4- or 5-pyrimidinyl, 1-, 2- or 4-imidazolyl, 2-, 4-, or 5-oxazolyl, 2-, 4-, or 5-thiazolyl, 1-, 3- or 4pyrazolyl, 1-, 3- or 4-triazolyl, 2-pyrazinyl, or 1-, 2- or 5-tetrazolyl, each of which is optionally mono- or disubstituted with halogen, trifluoromethyl, amino, lower alkyl, lower alkoxy, with the proviso that tetrazolyl can have at most one substituent;
Z1 is lower alkyl; and
V2, Y2 and A2 are as defined above; 
where
Z2 is carbon or nitrogen;
xe2x80x83where
when Z2 is CH, n is 0, 1, 2 or 3 and p is 1, 2, or 3,
R10 is carboxamido, or (lower alkylene)-G5xe2x80x94R11 
wherein G5 is NH, NH(lower alkyl) and R11 is hydrogen or lower alkyl;
when Z2 is carbon, n is 1 or 2 and p is 1 or 2, R10 is amino; or
when Z2 is nitrogen, n is 1 or 2 and p is 1 or 2, R10 is hydrogen; or
(iv) a nitrogen heterocycle of the formula: 
wherein the N-ring represents triazolyl, tetrazolyl, imidazolyl, or pyrazolyl, each of which is optionally substituted with amino, trifluoromethyl, carboxamido, or (lower alkylene)-G6xe2x80x94R12 wherein G6 is NH, NH(lower alkyl) and R12 is hydrogen or lower alkyl.
The compounds of Formula I are antagonists at the. CRF1 receptor and are useful in the diagnosis and treatment of stress related disorders such as post traumatic stress disorder (PTSD) as well as depression, headache and anxiety.